单细胞多组学剖析复发多发性骨髓瘤患者对 BCMA 嵌合抗原受体 T 细胞的反应和耐药性

IF 23.5 1区 医学 Q1 ONCOLOGY Nature cancer Pub Date : 2024-04-19 DOI:10.1038/s43018-024-00763-8
Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus H. Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Köhl, Uwe Platzbecker, Kristin Reiche, Vladan Vucinic, Maximilian Merz
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引用次数: 0

摘要

目前还缺少能预测复发/难治性多发性骨髓瘤患者对嵌合抗原受体(CAR)T细胞的反应和耐药性的标志物。我们在应用经批准的 B 细胞成熟抗原导向 CAR T 细胞前后,对从外周血和骨髓中分离的单核细胞进行了单细胞多组学分析,以确定与耐药性和早期复发相关的标记物。在进行白细胞清除时发现了应答者和非应答者之间的差异。无应答者的免疫抑制微环境表现为表达免疫检查点分子 CD39 的单核细胞数量增加,CD8+ T 细胞和自然杀伤细胞功能受到抑制。与低/中度扩增克隆相比,CAR T 细胞的分析表明,高扩增克隆具有细胞毒性和衰竭表型。我们确定了 CAR T 细胞的潜在免疫疗法靶点,如 PD1,以改善其功能和持久性。我们的工作提供了证据,证明免疫抑制微环境会导致多发性骨髓瘤患者对CAR T细胞疗法产生耐药性。
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Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma
Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma. Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.
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来源期刊
Nature cancer
Nature cancer Medicine-Oncology
CiteScore
31.10
自引率
1.80%
发文量
129
期刊介绍: Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.
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